RESEARCH ACCOMPLISHMENTS[unreadable] [unreadable] NOMID STUDIES:[unreadable] Neonatal-onset multisystem inflammatory disease (NOMID) is a rare autoinflammatory/ autoimmune disorder characterized by urticarial rash, fever, aseptic meningitis, papilledema, sensorineural hearing loss, epiphyseal overgrowth of the long bones, growth retardation, and, in some cases, mental impairment. NOMID is at the severe end of a spectrum of disorders caused by mutations in CIAS1, which encodes a protein, cryopyrin, that is a key regulator of interleukin 1 (IL-1) beta activation. [unreadable] Results over the last year:[unreadable] CLINICAL:[unreadable] 1. We analyzed 3 year outcome data in 20 patients with NOMID who have been receiving escalating doses of anakinra in the attempt to achieve clinical complete remission of inflammatory symptoms. The initially observed good clinical response persists and the drug is overall well tolerated. However, in 3 patients with severe hearing loss at the beginning of the study, hearing loss progressed and intermittent low grade leptomeningeal inflammation was seen in up to 50% of patients at 3 years. Although no new bone lesions occurred with anakinra treatment, preexisting bony lesions continued to expand on treatment.[unreadable] 2. We assessed disability on treatment with anakinra and have seen significant improvement in pain and motor disability but not cognitive function.[unreadable] 3. In untreated patients, the chronic inflammation leads to significant metabolic changes that include growth retardation, bone loss and anemia. We showed that bone mineral density increases above the age-expected increase and see a rapid and sustained change in bone markers that indicate an increase in bone production. Anemia rapidly resolves and catch-up height and weight gains are seen when the inflammation is suppressed. [unreadable] [unreadable] LABORATORY:[unreadable] 1. IL-1 secretion in CIAS1 mutation-positive and -negative patients differs when PBMCs are examined and a new mutation was identified in Dr Kastners laboratory in a patient who was thought to be mutation negative.[unreadable] 2. Dr Kastners laboratory identified a specific microarray signature that distinguishes NOMID patients from patients with other autoinflammatory diseases. The disease specific gene expression profile will allow us to define an IL-1 signature that may allow us to identify shared immune pathways in other yet uncharacterized inflammatory diseases. [unreadable] [unreadable] FCAS STUDY:[unreadable] 1. We have published long term outcome data in patients on the mild end of the spectrum of cryopyrin associated periodic syndromes (CAPS). IL-1 Trap, rilonacept (Acrolyst), is a long-acting IL-1 inhibitor and compared to anakinra, which is administered daily, rilonacept needs to be injected weekly. IL-1 Trap is effective in controlling inflammation in FCAS patients and a multicenter study based on our initial PK and PD data has been conducted and led to the FDA approval of rilonacept for the indication of FCAS and MWS. [unreadable] [unreadable] [unreadable] ADULT ONSET STILL'S STUDIES[unreadable] We have currently recruited 5 patients with adult-onset Still's disease (AOSD) who are also treated with rilonacept. Initial data indicates a less uniform response to rilonacept with inflammatory remission observed in 2 out of 5 patients. Biomarker studies that help distinguish patients with and without an immediate response to IL-1 blockade are ongoing.[unreadable] [unreadable] OTHER AUTOINFLAMMATORY DISEASES: [unreadable] Treatment with the IL-1 inhibitor, anakinra, of a patient with neonatal-onset multifocal osteomyelitis, periostitis and pustulosis and severe systemic inflammation who was hospital bound, led to rapid resolution of all inflammatory signs and symptoms and prompted evaluation of new mutations in the IL-1 pathway. In collaboration with Drs. Kastner and Ferguson, sequencing of candidate genes in the IL-1 signaling pathway led to the identification of so far 3 different mutations in the IL1RN gene. In 2 cases a homozygous frameshift mutation (N52KfsX25) and a missense mutation (E77X) lead to premature truncation of the IL-1 receptor antagonist protein. A third patient is homozygous for a 170kb deletion that includes the IL1RN gene. Functional studies confirmed absent or very low expression of the mutant protein and complete loss of function. LPS or IL-1beta stimulation lead to increased expression of the pro-inflammatory cytokines and chemokines, IL-6, IL-8, MIP-1 alpha, TNF, and MCP-1, which are associated with neutrophil activation and recruitment upon stimulation of whole blood cells from the 3 patients. All children have been unresponsive to several DMARDs including high doses of steroids but had a uniformly rapid clinical response with complete resolution of skin and bone lesions and complete normalization of inflammatory markers including ESR and CRP, leukocytosis, anemia and thrombocytosis within 7-14 days of treatment with the IL-1 receptor antagonist anakinra. Deficiency of the Interleukin-1 Receptor Antagonist, DIRA, is a novel autoinflammatory syndrome that exemplifies once more the crucial role of IL-1 and expands the organ- specific disease manifestations to aseptic osteomyelitis, periostitis, pustulosis and vasculitis (in one patient). [unreadable] [unreadable] [unreadable] CONCLUSIONS AND SIGNIFICANCE[unreadable] [unreadable] 1. In now 2 severe autoinflammatory syndromes, cryopyrin associated periodic syndromes, CAPS (which includes FACS, MWS and NOMID), and deficiency in IL-1 receptor syndrome, DIRA, the crucial role for IL-1 in the pathophysiology of these illnesses with multiorgan involvement has been demonstrated. [unreadable] 2. Our studies on the long-term treatment effect of IL-1 blockade in patients with NOMID indicate that treatment is safe and effective in the treatment of this devastating illness for at least up to 3 years and improves disability and retards/stops progression of hearing loss and vision loss. Patients treated with this agent for longer periods of time have continued to show significant improvement in their symptoms, and we will continue to evaluate patients for long term efficacy and safety. [unreadable] 3. A primary prevention protocol targets very young children with NOMID and will allow us to determine how effective early therapy is in the primary prevention of permanent organ damage that would develop if children remained untreated or partially treated with other DMARDs and steroids. [unreadable] 4. The development of long acting IL-1 inhibitors may allow for better disease control in those patients who are not in complete remission and offer more convenient treatment options particularly in children in whom daily injections can be quite traumatic. [unreadable] 5. The heterogeneous response to IL-1 blockade in patients with AOSD suggests a more complex cause for the inflammatory response in patients with AOSD. [unreadable] 6. The role of IL-1 in aseptic multifocal osteomyelitis, pustulosis, hyperostosis and vasculitis suggests the evaluation of the contribution of IL-1 in other diseases with overlapping clinical phenotypes and expands the spectrum of downstream IL-1 mediated organ manifestations to osteolytic bone lesions and skin pustulosis. These findings could also stimulate the evaluation of upstream IL-1 dysregulation in phenotypically related diseases such as pustular psoriasis, diseases with inflammatory skin and bone manifestations (skibo diseases), Behcet's disease and other forms of vasculitis such as panarteritis nodosa. [unreadable] 7. The phenotypic difference between NOMID and DIRA (no CNS, eye and ear inflammation in DIRA, compared to NOMID) and difference in skin manifestations, urticaria-like versus pustulosis, allow us to study the organ- specific immune responses downstream of IL-1 and may shed light on processes that determine specific organ manifestations.